Charcot-Marie-Tooth disease is a progressive chronic hereditary disease with damage to the peripheral nervous system, leading to muscular atrophy of the distal parts of the legs, and then the arms. Along with atrophy, hypesthesia and extinction of tendon reflexes, fascicular twitching of muscles are observed. Diagnostic measures include electromyography, electroneurography, genetic counseling and DNA diagnostics, nerve and muscle biopsy. Symptomatic treatment — courses of vitamin therapy, anticholinesterase, metabolic, antioxidant and microcirculatory therapy, physical therapy, massage, physiotherapy and hydrotherapy.
ICD 10
G60.0 Hereditary motor and sensory neuropathy
General information
Charcot-Marie-Tooth disease (SMTD) belongs to a group of progressive chronic hereditary polyneuropathies, which includes Russi-Levy syndrome, Dejerin-Sott hypertrophic neuropathy, Refsum’s disease and other more rare diseases.
According to various data, Charcot-Marie-Tooth disease occurs with a frequency of 2 to 36 cases per 100 thousand population. Often the disease is of a family nature, and in members of the same family, clinical manifestations may have different severity. Along with this, sporadic variants of SMTD are also observed. Men get sick more often than women.
Causes
To date, practical neurology as a science does not have reliable information about the etiology and pathogenesis of neural amyotrophy. Studies have shown that 70-80% of patients with SMTD who underwent genetic examination had duplication of a certain section of the 17th chromosome. It was determined that Charcot-Marie-Tooth neural amyotrophy has several forms, probably caused by mutations of various genes. For example, the researchers found out that in the form of SMTD caused by a mutation of the MFN2 gene encoding the mitochondrial protein, a clot of mitochondria forms, disrupting their movement along the axon.
Charcot-Marie-Toute disease is characterized by autosomal dominant inheritance with a penetrance of 83%. There are also cases of autosomal recessive inheritance.
Pathogenesis
It has been established that most forms of SMTD are associated with damage to the myelin sheath of peripheral nerve fibers, forms with pathology of axons — axial cylinders passing in the center of the nerve fiber are less common. Degenerative changes also affect the anterior and posterior roots of the spinal cord, neurons of the anterior horns, Goll’s pathways (spinal pathways of deep sensitivity) and Clark’s pillars related to the posterior cerebrospinal tract.
Secondarily, as a result of impaired peripheral nerve function, muscle atrophy develops, affecting individual groups of myofibrils. Further progression of the disease is characterized by displacement of the nuclei of the sarcolemma, hyalinization of the affected myofibrils and interstitial growth of connective tissue. Subsequently, the increasing hyaline degeneration of myofibrils leads to their disintegration.
Classification
In modern neurological practice, Charcot-Marie-Tooth disease is divided into 2 types. Clinically, they are almost homogeneous, but they have a number of features that allow such a distinction to be made.
Type I neural amyotrophy is characterized by a significant decrease in the rate of nerve impulse conduction. Nerve biopsy reveals segmental demyelination of nerve fibers, hypertrophic growth of unaffected Schwann cells;
With type II amyotrophy, the speed of conduction suffers slightly, biopsy analysis shows axon degeneration.
The connection between Charcot-Marie-Tooth disease and Friedreich’s ataxia was noted. In some cases, patients with SMTD eventually show typical signs of Friedreich’s disease and vice versa — sometimes, after many years, the clinic of Friedreich’s ataxia is replaced by symptoms of neural amyotrophy. Some authors have given descriptions of intermediate forms of these diseases. There have been cases when some family members were diagnosed with Friedreich’s ataxia, and others with amyotrophy of SMTD.
Symptoms
Charcot-Marie-Tooth disease begins with the development of symmetrical muscular atrophy in the distal parts of the legs. The initial symptoms manifest, as a rule, in the first half of the second decade of life, less often in the period from 16 to 30 years. They consist in increased fatigue of the feet, if necessary, to stand in one place for a long time. At the same time, there is a symptom of “trampling” – in order to relieve fatigue of the feet, the patient resorts to walking on the spot.
In some cases, neural amyotrophy manifests itself with sensitivity disorders in the feet, most often with paresthesia in the form of crawling goosebumps. A typical early sign of SMTD is the absence of achilles, and later knee tendon reflexes. The main symptom that patients most often pay attention to themselves is paroxysmal painful contractions in the calf muscles (cramps), which intensify at night or after prolonged physical exertion.
Initially developing atrophy affects primarily the abductors and extensors of the foot. The result is a drooping foot, the inability to walk on the heels and a peculiar gait resembling the pacing of a horse — steppage. Next, the adductor muscles and flexors of the foot are affected. Total atrophy of the foot muscles leads to its deformation with a high arch, like Friedreich’s foot; hammer-shaped toes of the foot are formed. Gradually, the atrophic process passes to the more proximal parts of the legs — the lower legs and the lower thighs. As a result of atrophy of the muscles of the lower leg, a dangling foot occurs. Due to the atrophy of the distal parts of the legs, with the preservation of the muscle mass of the proximal parts, the legs take the form of inverted bottles.
Often, with the further progression of Charcot-Marie-Tooth disease, atrophy appears in the muscles of the distal parts of the hands — first in the hands, and then in the forearms. Due to the atrophy of the hypotenar and tenar, the brush becomes like a monkey’s paw. The atrophic process never affects the muscles of the neck, trunk and shoulder girdle.
Often, Charcot-Marie-Tooth disease is accompanied by mild fascicular twitching of the muscles of the arms and legs. Compensatory hypertrophy of the muscles of the proximal extremities is possible. Sensory disorders in neural amyotrophy are characterized by total hypesthesia, however, surface sensitivity (temperature and pain) suffers significantly more than deep. In some cases, cyanosis and swelling of the skin of the affected extremities are observed.
Charcot-Marie-Toute disease is characterized by a slow progression of symptoms. The period between the clinical manifestation of the disease from the lesion of the legs and before the appearance of atrophy on the hands can be up to 10 years. Despite the pronounced atrophy, patients maintain a working condition for a long time. Various exogenous factors can accelerate the progression of symptoms: a previous infection (measles, infectious mononucleosis, rubella, sore throat, ARVI), hypothermia, TBI, spinal cord injury, hypovitaminosis.
Complications
Charcot-Marie-Tooth disease is characterized by early disability. Due to the progressive atrophy of the distal extremities and pronounced sensitivity disorders, patients gradually lose the ability to walk independently. Due to gross deformities of the hands, patients cannot serve themselves. Joint contractures often require surgical correction.
At an early stage of the disease, weakness in the leg muscles, hypesthesia and hyporeflexia lead to frequent falls, which increases the likelihood of injuries and fractures. The most serious adverse effects occur when Charcot-Marie-Tooth disease and Friedreich’s ataxia are combined. These include blindness, cardiomyopathy, respiratory failure.
Diagnostics
The patients are supervised by neurologists and orthopedists. When interviewing the patient, the age at which symptoms began to appear is specified (for the disease of SCHMT, manifestation at 15-25 years is typical). A family history (the presence of a close relative with this pathology) is important. During the general examination, attention is drawn to the change in gait, deformation of the feet and hands.
During neurological examination, there is a decrease in the tone of the distal parts of the upper and lower extremities, a weakening or complete absence of tendon reflexes (achilles, knee), a decrease in skin sensitivity. To clarify the diagnosis, the following research methods are carried out:
- ENMG. With electroneuromyography, signs of axonal and demyelinating neuropathy are noted – a slowdown in the speed of the pulse along the motor nerves, a drop in the amplitude of M-responses.
- Computer pallesthesiometry. This diagnostic procedure allows you to objectively assess the decrease in vibration sensitivity – the earliest signs of SMTD disease.
- Histology. Histological examination of the biopsy of the tibial nerve reveals a decrease in the number of myelin fibers, proliferation of connective tissue fibers, atrophy of myelin.
- DNA analysis. A confirmatory research method that verifies the diagnosis. Duplications of the peripheral myelin protein (PMP22) gene on chromosome 17 are detected.
The differential diagnosis of Charcot-Marie-Tooth disease should be carried out with hereditary neuromuscular diseases (Werdnig-Hoffman spinal muscular atrophy, adrenoleukodystrophy, Peliceus-Merzbacher disease) and acquired chronic polyneuropathies (Guillain-Barre syndrome).
Treatment
Drug therapy
To undergo treatment, all patients are subject to mandatory hospitalization in a hospital. Currently, there is no specific therapy that can slow the progression of axonal degeneration and demyelination. However, timely initiated competent and individually selected therapy can significantly improve the quality of life of patients. Of the medications used for the symptomatic treatment of neural amyotrophy of SMT:
- Vitamins. Injections of B vitamins (B1, B3, B12) are prescribed to improve microcirculation and restore nerve fibers. Vitamin B6 should be treated with caution, since exceeding its dose has a neurotoxic effect. According to some researchers, ascorbic acid is able to suppress the formation of peripheral myelin protein (PMP22).
- Muscle relaxants. In order to eliminate painful muscle contractions, patients are recommended to take medications that relax skeletal muscles – baclofen, tolperizone.
- Calcium and vitamin D. Since approximately 40% of patients have osteoporosis, to reduce the risk of fractures, they are shown calcium and vitamin D preparations (cholecalciferol).
- Anticholinesterase agents. In case of type 2 SCHMT disease, it is advisable to prescribe proserin, galantamine to improve neuromuscular conduction.
Non-drug therapy
The main attention is paid to the non-drug treatment of Charcot-Marie-Tooth disease. To achieve the maximum therapeutic effect, a set of the following measures is used:
- Electrical stimulation. To enhance neurotrophy, activation of metabolism in paretic muscles and conduction of peripheral nerves, a directional supply of electrical impulses is used.
- Physical therapy. In order to increase muscle tone, regular physical therapy classes are recommended. The most effective combination of active (performed by the patient himself) and passive (performed by a specialist) exercises.
- Massage. To improve blood circulation and lymph outflow in the muscles (primarily the lower extremities), various types of massage are performed – manual (stimulating, relaxing) and hardware (vibration massage).
- Balneotherapy. Mud baths and mud applications contribute to the correction of disorders of the autonomic nervous system and slow down the formation of contractures.
- Orthopedic treatment. To prevent the development of gross deformities, patients are prescribed to wear orthopedic shoes. When joints are unstable due to muscle weakness, special devices (orthoses, braces) are used to fix the feet in a given position.
Comprehensive implementation of these measures allows you to increase muscle strength, correct balance and gait disorders. Thanks to this, it is possible to increase the household, social adaptation, and working capacity of patients.
Surgical treatment
With pronounced atrophic phenomena and deformities of the foot, which significantly complicate independent walking, when conservative methods are unsuccessful, orthopedic surgical interventions are indicated – metatarsal osteotomy, osteotomy of the calcaneus. In some cases, arthrodesis may be necessary to restore the supporting function of the foot.
Experimental treatment
The search for an effective drug to combat Charcot-Marie-Tooth disease continues. In clinical trials where patients took the drug PXT3003 (a combination of small doses of baclofen, naltrexone and sorbitol), positive results were noted in the form of increased muscle strength, renewed sensitivity and tendon reflexes.
The possibility of using HDAC6 inhibitors, enzymes that stimulate the regeneration of nerve cell cytoskeleton proteins, as a treatment is being considered. Experiments on laboratory animals have shown that these substances can significantly slow the progression of demyelination and axonal degeneration.
Prognosis and prevention
Charcot-Marie-Tooth disease is a severe disabling disease. Most patients lose the ability to walk 15-20 years after the onset of symptoms. However, due to the fact that the distal parts of the extremities are mainly affected, the life expectancy of patients practically does not differ from that in the general population.
Fatal outcomes in young and middle age are observed in combination with Friedreich’s ataxia, when the respiratory muscles and myocardium are involved in the pathological process. There are no specific methods of primary prevention. Timely initiation of complex therapy allows you to prevent the development of complications and maximize efficiency.